Advanced human immunodeficiency virus (HIV) invection is frequently associated with cognitive impairment, and the response to highly active antiretroviral therapy (HAART) is often partial or associated with intoleable side effects. Recent studies suggest that oxygen radical production within the CNS may play an important role in the pathogenesis of HIV dementia. Selegiline, at very low dosages, has a trophic effect on injured neurons in vitro and vivo, and may prevent an increase in oxygen radicals associated with injury. We conducted a randomized, double-blind, placebo-controlled clinical trial of a trandsdermal administratiion of selegiline in HIV seropositive (HIV+) patients to assess its safety and tolerablilty, and to assess its impact on HIV-associated cognitive impairment. Both selegiline and placebo were well tolerated with few asverse events. Subjects receiving selegiline performed significatly better on the Rey Auditory Verbal Learning Test delayed recall, with improvement in the selegiline group by 2.6 words compared to -0.3 words in the placebo group (p=0.3). The treatment effect favoring selegiline also was significant (p=0.03) for the Grooved Pegboard dominant hand. In addition, on the macroneurologic exam score, the selegiline group improved by 3 points, whereas the placebo group deteriorated by 2.5 points (p=0.03). These results suggest that selegiline may improve verbal memory and motor performance in subjects with mild HIV-associated cognitive.